Programmed cell death 4 mechanism of action: The model to be updated?

Abstract

Programmed cell death 4 (Pdcd4) is frequently suppressed in tumors of various origins and its suppression correlates with tumor progression. Pdcd4 inhibits cap-dependent translation from mRNAs with highly structured 5'-regions through interaction with the eukaryotic translation initiation factor 4A (eIF4A) helicase and a target transcript. Decrease in Pdcd4 protein is believed to provide a relief of otherwise suppressed eIF4A-dependent translation of proteins facilitating tumor progression. However, it remains unknown if lowered Pdcd4 levels in cells suffices to cause a relief in translation inhibition through appearance of the Pdcd4-free translation-competent eIF4A protein, or more complex and selective mechanisms are involved. Here we showed that eIF4A1, the eIF4A isoform involved in translation, significantly over-represents Pdcd4 both in cancerous and normal cells. This observation excludes the possibility that cytoplasmic Pdcd4 can efficiently exert its translation suppression function owing to excess of eIF4A, with Pdcd4-free eIF4A being in excess over Pdcd4-bound translation-incompetent eIF4A, thus leaving translation from Pdcd4 mRNA targets unaffected. This contradiction is resumed in the proposed model, which supposes initial complexing between Pdcd4 and its target mRNAs in the nucleus, with subsequent transport of translation-incompetent, Pdcd4-bound target mRNAs into the cytoplasm. Noteworthy, loss of nuclear Pdcd4 in cancer cells was reported to correlate with tumor progression, which supports the proposed model of Pdcd4 functioning.

eIF4A/PDCD4 Pathway, a Factor for Doxorubicin Chemoresistance in a Triple-Negative Breast Cancer Cell Model

“…PDCD4 appeared to be mainly localized in the cytoplasmic fraction of both the parental and variant B cells, suggesting that the activity of this protein was primarily cytosolic. In cancer cells, decreases in nuclear PDCD4 have been correlated with tumor progression [ 56 ]. In line with this notion, MMP-9 expression could depend on the transcription factor AP-1, a heterodimer composed of c-Fos and c-Jun.…”

PDCD4 Is an Androgen-Repressed Tumor Suppressor that Regulates Prostate Cancer Growth and Castration Resistance

“…PDCD4 binds and inhibits the eukaryotic translation initiation factor and RNA helicase, eIF4A (33)(34)(35). It has been proposed that PDCD4 regulates gene transcripts with complex 5 0 UTRs through two possible mechanisms, by directly binding and sequestering eIF4A, and separately, by binding nuclear mRNAs and preventing their transfer to the cytoplasm (36). Cap-dependent translation initiation, through eIF4A, regulates the expression of several cancer-associated genes, including c-Myc, cyclins, and PARP (28,37,38).…”

Mechanisms of the Epithelial–Mesenchymal Transition and Tumor Microenvironment in Helicobacter pylori-Induced Gastric Cancer

“…Programmed cell death protein 4 (PDCD4) is a tumor suppressor responsible for the inhibition of cell growth, tumor invasion, metastasis, or induction of apoptosis [213]. It is localized in the nucleus of proliferating cells and binds to the eukaryotic initiation factor-4A (eIF4A) or eukaryotic translation initiation factor 4 G (eIF4G), inhibiting translation [214,215]. PDCD4 controls the inhibition of cancer invasion by regulating the expression of mitogen-activated protein 4 kinases 1 or urokinase plasminogen activator receptor [216].…”